Functional Adaptation of LPS-affected Dentoalveolar Fibrous Joints in Rats.

INTRODUCTION: The functional interplay between cementum of the root and alveolar bone of the socket is tuned by a uniquely positioned 70-80 µm wide fibrous and lubricious ligament in a dentoalveolar joint (DAJ). In this study, structural and biomechanical properties of the DAJ, periodontal ligament space (PDL-space also known as the joint space), alveolar bone of the socket, and cementum of the tooth root that govern the biomechanics of a lipopolysaccharide (LPS)-affected DAJ were mapped both in space and time. METHODS: The hemi-maxillae from 20 rats (4 control at 6 weeks of age, 4 control and 4 LPS-affected at 12 weeks of age, 4 control and 4 LPS-affected at 16 weeks of age) were investigated using a hybrid technique; micro-X-ray computed tomography (5 µm resolution) in combination with biomechanical testing in situ. Temporal variations in bone and cementum volume fractions were evaluated. Trends in mineral apposition rates (MAR) in additional six Sprague Dawley rats (3 controls, 3 LPS-affected) were revealed by transforming spatial fluorochrome signals to functional growth rates (linearity factor - RW) of bone, dentin, and cementum using a fast Fourier transform on fluorochrome signals from 100-µm hemi-maxillae sections. RESULTS: An overall change in LPS-affected DAJ biomechanics (a 2.5-4.5X increase in tooth displacement and 2X tooth rotation at 6 weeks, no increase in displacement and a 7X increase in rotation at 12 weeks; 27% increase in bone effective strain at 6 weeks and 11% at 12 weeks relative to control) was associated with structural changes in the coronal regions of the DAJ (15% increase in PDL-space from 0 to 6 weeks but only 5% from 6 to 12 weeks compared to control). A significant increase (p < 0.05) in PDL-space between ligated and age-matched control was observed. The bone fraction of ligated at 12 weeks was significantly lower than its age-matched control, and no significant differences (p > 0.05) between groups were observed at 6 weeks. Cementum in the apical regions grew faster but nonlinearly (11% and 20% increase in cementum fraction (CF) at 6 and 12 weeks) compared to control. Alveolar bone revealed site-specific nonlinear growth with an overall increase in MAR (108.5 µm/week to 126.7 µm/week after LPS treatment) compared to dentin (28.3 µm/week in control vs. 26.1 µm/week in LPS-affected) and cementum (126.5 µm/week in control vs. 119.9 µm/week in LPS-affected). A significant increase in CF (p < 0.05) in ligated specimens was observed at 6 weeks of age. CONCLUSIONS: Anatomy-specific responses of cementum and bone to the mechano-chemo stimuli, and their collective temporal contribution to observed changes in PDL-space were perpetuated by altered tooth movement. Data highlight the "resilience" of DAJ function through the predominance of nonlinear growth response of cementum, changes in PDL-space, and bone architecture. Despite the significant differences in bone and cementum architectures, data provided insights into the reactionary effects of cementum as a built-in compensatory mechanism to reestablish functional competence of the DAJ. The spatial shifts in architectures of alveolar bone and cementum, and consequently ligament space, highlight adaptations farther away from the site of insult, which also is another novel insight from this study. These adaptations when correlated within the context of joint function (biomechanics) illustrate that they are indeed necessary to sustain DAJ function albeit being pathological.

Alzheimer disease and the periodontal patient: New insights, connections, and therapies.

Loss of cognitive function in the aging population, particular those with Alzheimer disease, presents unique challenges to health practitioners. For the dental practitioner these include management of periodontal diseases, caries, and other dental conditions in this special population. It is well established in the cognitively impaired patient that a lack of adherence to dental hygiene routines and professional care leads to increases in the prevalence and severity of these dental conditions, leading to increased loss of teeth. More recent evidence has indicated a possible role of the microbiota of dental plaque associated with periodontal diseases in the development and progression of Alzheimer disease, thereby supporting a two-way interaction of these two diseases. New therapies are needed to address the potential upstream events that may precede overt signs of Alzheimer disease. One of these approaches would be to target these various bacterial, viral, and other microbial pathogens associated with periodontal disease that can translocate into the bloodstream and then to distal sites, such as the brain. Such microbial translocation would lead to local inflammation and buildup of the hallmark signs of Alzheimer disease, including amyloid beta deposits, tau fragmentation and tangles, breakdown of host protective molecules, such as the apolipoproteins, and neuron toxicity. In this review, evidence for the biological basis of the role of the periodontal disease microflora on the initiation and progression of Alzheimer disease will be presented with a focus on the potential role of the keystone pathogen Porphyromonas gingivalis with its family of gingipain enzymes. The various mechanisms for which P. gingivalis gingipains may contribute to the initiation and progression of Alzheimer disease are presented. Small-molecule inhibitors of these gingipains and their effects on reducing biological markers of Alzheimer disease may have beneficial effects for the initiation and progression of loss of cognitive function in Alzheimer disease. In addition to these targeted therapies for specific periodontal pathogens, considerations for the dental practitioner in applying more general approaches to reducing the periodontal plaque microflora in the management of the cognitively impaired patient are discussed for this special population.

Salivary metabolite levels in perinatally HIV-infected youth with periodontal disease.

INTRODUCTION: Salivary metabolite profiles are altered in adults with HIV compared to their uninfected counterparts. Less is known about youth with HIV and how oral disorders that commonly accompany HIV infection impact salivary metabolite levels. OBJECTIVE: As part of the Adolescent Master Protocol multi-site cohort study of the Pediatric HIV/AIDS Cohort Study (PHACS) network we compared the salivary metabolome of youth with perinatally-acquired HIV (PHIV) and youth HIV-exposed, but uninfected (PHEU) and determined whether metabolites differ in PHIV versus PHEU. METHODS: We used three complementary targeted and discovery-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) workflows to characterize salivary metabolite levels in 20 PHIV and 20 PHEU youth with and without moderate periodontitis. We examined main effects associated with PHIV and periodontal disease, and the interaction between them. RESULTS: We did not identify differences in salivary metabolite profiles that remained significant under stringent control for both multiple between-group comparisons and multiple metabolites. Levels of cadaverine, a known periodontitis-associated metabolite, were more abundant in individuals with periodontal disease with the difference being more pronounced in PHEU than PHIV. In the discovery-based dataset, we identified a total of 564 endogenous peptides in the metabolite extracts, showing that proteolytic processing and amino acid metabolism are important to consider in the context of HIV infection. CONCLUSION: The salivary metabolite profiles of PHIV and PHEU youth were overall very similar. Individuals with periodontitis particularly among the PHEU youth had higher levels of cadaverine, suggesting that HIV infection, or its treatment, may influence the metabolism of oral bacteria.

Periodontics in the USA: An introduction.

The United States continues to be an incubator for new concepts and approaches to the diagnosis, treatment, and prevention of periodontal diseases. This volume of Periodontology 2000 presents some of these newer areas of research and paradigms that have emerged in the United States from both long-established and new investigators. These areas include: (1) more comprehensive approaches to assessing the total periodontal microbiome, including bacteria, viruses, and fungi, and their interactions with both the local and systemic inflammatory and immune responses, as well as with other oral and systemic conditions and diseases; (2) new developments for a more comprehensive characterization of the patient genome, transcriptome, and proteome profiles and the role of these profiles in periodontal disease pathogenesis; (3) new developments in nonsurgical approaches to periodontal diseases, including broad-based lines of attack using natural antimicrobials and host-modulation therapies and more focused approaches that target specific interactions in the host response; and (4) new big data analysis, machine learning, and imaging approaches, both for understanding the pathogenesis of periodontal diseases and for developing improved risk-assessment tools and better treatment outcomes.

Current trends and new developments in HIV research and periodontal diseases.

With the advent of combined antiretroviral therapies, the face of HIV infection has changed dramatically from a disease with almost certain mortality from serious comorbidities, to a manageable chronic condition with an extended lifespan. In this paper we present the more recent investigations into the epidemiology, microbiology, and pathogenesis of periodontal diseases in patients with HIV, and the effects of combined antiretroviral therapies on the incidence and progression of these diseases both in adults and perinatally infected children. In addition, comparisons and potential interactions between the HIV-associated microbiome, host responses, and pathogenesis in the oral cavity with the gastrointestinal tract and other areas of the body are presented. Also, the effects of HIV and combined antiretroviral therapies on comorbidities such as hyposalivation, dementia, and osteoporosis on periodontal disease progression are discussed.

Biomechanical pathways of dentoalveolar fibrous joints in health and disease.

Spatial and temporal adaptations within periodontal tissues and their interfaces result from functional loads. Functional loads can be physiologic and/or pathologic in nature. The prolonged effect of these loads can alter the overall biomechanics of a dentoalveolar fibrous joint (dentoalveolar joint) by changing the form of the tooth root and its socket. This "sculpting" of the tooth root and alveolar bony socket is a consequence of several mechano-biological changes that occur within the periodontal complex of a load-bearing dentoalveolar joint. These include changes in biochemical expressions, structure, elemental composition, and mechanical properties of alveolar bone, the underlying tissues of the roots of teeth, and their interfaces. These physicochemical changes in tissues continue to prompt mechano-responsive biochemical activities at the attachment sites of periodontal ligament (soft) with bone (hard), and ligament with cementum (hard), which are the entheses of a load-bearing dentoalveolar joint. Forces at soft-hard tissue attachment sites between disparate materials with different stiffness values theoretically generate strain singularities or discontinuities. These discontinuities under prolonged functional loading increase the probability for failure to occur specifically at the enthesial zones. However, in a normal dentoalveolar joint, gradual stiffness gradients exist from ligament to bone, and from ligament to cementum. The gradual transitions in stiffness from softer ligament (lower stiffness) to harder bone or cementum (higher stiffness) or vice versa optimize tissue and interfacial strains. Optimization of tissue and ligament-enthesial physical and chemical properties facilitates transmission of cyclic forces of varying magnitudes and frequencies that collectively maintain the overall biomechanics of a dentoalveolar joint. The objectives of this review are 3-fold: (i) to illustrate physicochemical adaptations at the periodontal ligament entheses of a human periodontal complex affected by subgingival calculus; (ii) to demonstrate how to "program" the hallmarks of periodontitis in small-scale vertebrates in vivo to generate spatiotemporal maps of physicochemical adaptations in a diseased dentoalveolar joint; and (iii) to correlate dentoalveolar joint biomechanics in healthy and diseased states to spatiotemporal maps of physicochemical adaptations within respective periodontal tissues. This interdisciplinary approach demonstrates that physicochemical adaptations within periodontal tissues using the mechanics of materials (tissue mechanics), materials science (tissue composition), and mechano-biology (matrix molecules) can help explain the mechano-adaptation of dentoalveolar joints in normal and diseased functional states. Multiscale biomechanics and mechano-biology approaches can provide insights into the functional competence of a diseased relative to a normal dentoalveolar joint. Insights gathered from interdisciplinary and multiscale biomechanics approaches include the following: (i) physiologic loads related to chewing maintain a balance between mineral-forming and-resorbing biochemical cellular events, resulting in gradual stiffness gradients at the periodontal ligament entheses, and, in turn, sustain the overall biomechanics of a normal "healthy" dentoalveolar joint; (ii) pathologic loads resulting from tissue degradation and physical changes to the periodontal complex promote an abrupt stiffness gradient at the periodontal ligament entheses. The shift from gradual to an abrupt stiffness gradient could prompt a shift in the biochemical cascades, exacerbate mechano-responsive biochemical expressions at periodontal ligament entheses farther away from the site of insult, and culminate in joint degradation; (iii) sustained pathologic function on periodontally diseased joints exacerbates degradation of periodontal ligament entheses providing insights into "rescue therapy", such as the use of an adequate "mechanocal dose" to regain joint function; and (iv) spatiotemporal maps of changes in biochemical expressions, and physicochemical properties of strain-dominated affected sites, including the periodontal ligament entheses, can guide anatomy-specific therapeutics for tissue regeneration and/or disease control with the purpose of regaining dentoalveolar joint function. Modulation of occlusal loads could minimize disease progression and potentially assist in regaining functional attachment of ligament to bone and/or ligament to cementum of the dentoalveolar joint. Elucidating mechanisms that drive the breakdown of the functionally active periodontal complex burdened with microbes will provide the required critical insights into regenerative medicine and/or biomimetic approaches that would facilitate rescue/regain of dentoalveolar joint function.

Microbial biogeography and ecology of the mouth and implications for periodontal diseases.

In humans, the composition of microbial communities differs among body sites and between habitats within a single site. Patterns of variation in the distribution of organisms across time and space are referred to as "biogeography." The human oral cavity is a critical observatory for exploring microbial biogeography because it is spatially structured, easily accessible, and its microbiota has been linked to the promotion of both health and disease. The biogeographic features of microbial communities residing in spatially distinct, but ecologically similar, environments on the human body, including the subgingival crevice, have not yet been adequately explored. The purpose of this paper is twofold. First, we seek to provide the dental community with a primer on biogeographic theory, highlighting its relevance to the study of the human oral cavity. We summarize what is known about the biogeographic variation of dental caries and periodontitis and postulate that disease occurrence reflects spatial patterning in the composition and structure of oral microbial communities. Second, we present a number of methods that investigators can use to test specific hypotheses using biogeographic theory. To anchor our discussion, we apply each method to a case study and examine the spatial variation of the human subgingival microbiota in 2 individuals. Our case study suggests that the composition of subgingival communities may conform to an anterior-to-posterior gradient within the oral cavity. The gradient appears to be structured by both deterministic and nondeterministic processes, although additional work is needed to confirm these findings. A better understanding of biogeographic patterns and processes will lead to improved efficacy of dental interventions targeting the oral microbiota.

Biomarkers of oral inflammation in perinatally HIV-infected and perinatally HIV-exposed, uninfected youth.

AIM: To examine oral biomarkers that have been associated with periodontal disease progression in HIV-infected adults in perinatally HIV-infected and HIV-exposed but uninfected youth. MATERIAL AND METHODS: This was a cross-sectional, multicentre substudy of youth participating in the Oral Health Pediatric HIV/AIDS Cohort study. Gingival crevicular fluid repository samples from participants with and without periodontal disease (using Gingival Index [GI] and Bleeding on Probing [BOP] parameters on dental examination) were tested for concentration levels of inflammatory biomarkers. Associations were assessed using Wilcoxon test and Spearman correlation. RESULTS: For perinatal HIV youth (n = 129), the markers consistently elevated (p < .05) in sites with GI ≥2 and in sites with BOP were interleukin-1ß, 6 and 13, macrophage inflammatory protein-1α and metalloproteinase-9. Serum tumour necrosis factor-α and soluble CD14 were positively correlated with a summary count of elevated cytokines. No associations were seen among HIV-uninfected subjects (n = 71). CONCLUSIONS: The association of oral biomarkers of inflammation with clinical indicators of periodontal inflammation and systemic immune activation suggests that perinatal HIV-infected youth may be at higher risk for developing significant periodontal disease, associated with tooth loss and HIV progression. More frequent dental care of this group is needed to prevent potential periodontal progression.

Personalized periodontal treatment for the tobacco- and alcohol-using patient.

The use of various forms of tobacco is one of the most important preventable risk factors for the incidence and progression of periodontal disease. Tobacco use negatively affects treatment outcomes for both periodontal diseases and conditions, and for dental implants. Tobacco-cessation programs can mitigate these adverse dental treatment outcomes and may be the most effective component of a personalized periodontal treatment approach. In addition, heavy alcohol consumption may exacerbate the adverse effects of tobacco use. In this review, the microbiology, host/inflammatory responses and genetic characteristics of the tobacco-using patient are presented as a framework to aid the practitioner in developing personalized treatment strategies for these patients. These personalized approaches can be used for patients who use a variety of tobacco products, including cigarettes, cigars, pipes, smokeless tobacco products, e-cigarettes and other tobacco forms, as well as patients who consume large amounts of alcohol. In addition, principles for developing personalized tobacco-cessation programs, using both traditional and newer motivational and pharmacological approaches, are presented.

Prevalence of periodontal diseases in a multicenter cohort of perinatally HIV-infected and HIV-exposed and uninfected youth.

AIMS: To compare the prevalence and severity of periodontal diseases between 180 perinatally HIV-infected (PHIV) and 118 perinatally HIV-exposed and uninfected (PHEU) youth in a cross-sectional study conducted at 11 clinical sites in the United States and Puerto Rico from the Adolescent Master Protocol study of the Pediatric HIV/AIDS cohort study (PHACS) network. METHODS: Several analyses were conducted, employing the current CDC/AAP classification for periodontitis and incorporating a definition of gingivitis based on a bleeding on probing (BOP) threshold, and analyses based on more detailed whole-mouth, intra-oral regionally, site-based and tooth-based criteria of BOP, plaque levels, pockets depths and clinical attachment levels. RESULTS: After adjusting for plaque control habits and behavioural and sociodemographic factors, there were no significant differences in periodontal diseases between the PHIV and PHEU youth using any of these criteria. For PHIV youth, there was no significant association between parameters of periodontal disease and current HIV status. CONCLUSIONS: Although no significant differences in periodontal parameters were noted between the PHIV and PHEU youth, the influence of antiretroviral therapy merits further exploration in this cohort in a longitudinal study.

Oral Human Papillomavirus in Youth From the Pediatric HIV/AIDS Cohort Study.

In contrast to high rates of oral human papillomavirus (HPV) found in human immunodeficiency virus (HIV)-infected adults, only 2% of 209 perinatally HIV-infected youth had oral HPV. This rate was similar in HIV-exposed but uninfected youth. No association was found with sexual activity; however, low CD4 counts were associated with oral HPV.

Minimally invasive periodontal therapy for general practitioners.

There remains a high prevalence of mild-to-moderate forms of periodontal diseases in both developed and developing countries. Although many periodontal specialty practices currently place strong emphasis on implant surgery, periodontal plastic surgery and esthetics, general dentists and hygienists have often assumed more responsibility than periodontal specialty practices for the diagnosis, treatment, assessment and maintenance, and possible referral, of their patients. To address these current trends and challenges, this volume of Periodontology 2000 presents a series of topics on the basic biological principles of periodontal disease, as well as on approaches to diagnosis, treatment planning and treatment, in what is called 'conservative' or 'noninvasive' periodontal therapy. These topics include risk assessment of the periodontal condition; reduction, elimination and/or control of etiologies and risk factors, including mechanical, antimicrobial and host-modulation approaches; considerations for evaluation of clinical outcomes based on treatment approaches; and selected topics in laser therapy, halitosis and gingival recession.

The tobacco-using periodontal patient: role of the dental practitioner in tobacco cessation and periodontal disease management.

Although the prevalence of tobacco use has declined in some parts of the world, tobacco use remains a persistent and, in some cases, growing problem that will continue to be a fundamental challenge facing dental practitioners in the decades ahead. Dental practitioners have a unique opportunity and professional obligation to be a positive influence in reducing the economic and social burden inflicted by tobacco use on dental and general health. In this article, the current noninvasive, evidence-based approaches are presented for dental practitioners to help patients avoid initiating tobacco use, to encourage and assist patients in ceasing tobacco use and to address tobacco-induced damage to periodontal supporting tissues.

Effects of early vitamin D deficiency rickets on bone and dental health, growth and immunity.

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children's Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency.

Aging Periodontium, Aging Patient: Current Concepts.

A functioning natural dentition is essential to maintaining overall health in the elderly patient. While age-related alterations in periodontal tissues and the immune system may make an elderly patient more susceptible to periodontal breakdown, age itself is not a major risk factor for periodontal diseases. Rather, individual age-associated factors such as systemic diseases, medications and changes in behavior, motor function and cognitive function should be considered for each elderly patient when making treatment decisions.

Periodontal disease in HIV/AIDS.

Since the early 1990's, the death rate from AIDS among adults has declined in most developed countries, largely because of newer antiretroviral therapies and improved access to these therapies. In addition, from 2006 to 2011, the total number of new cases of HIV infection worldwide has declined somewhat and has remained relatively constant. Nevertheless, because of the large numbers of existing and new cases of HIV infection, the dental practitioner and other healthcare practitioners will still be required to treat oral and periodontal conditions unique to HIV/AIDS as well as conventional periodontal diseases in HIV-infected adults and children. The oral and periodontal conditions most closely associated with HIV infection include oral candidiasis, oral hairy leukoplakia, Kaposi's sarcoma, salivary gland diseases, oral warts, other oral viral infections, linear gingival erythema and necrotizing gingival and periodontal diseases. While the incidence and prevalence of these oral lesions and conditions appear to be declining, in part because of antiretroviral therapy, dental and healthcare practitioners will need to continue to diagnose and treat the more conventional periodontal diseases in these HIV-infected populations. Finding low-cost and easily accessible and acceptable diagnostic and treatment approaches for both the microbiological and the inflammatory aspects of periodontal diseases in these populations are of particular importance, as the systemic spread of the local microbiota and inflammatory products of periodontal diseases may have adverse effects on both the progression of HIV infection and the effectiveness of antiretroviral therapy approaches. Developing and assessing low-cost and accessible diagnostic and treatment approaches to periodontal diseases, particularly in developing countries, will require an internationally coordinated effort to design and conduct standardized clinical trials.

Porphyromonas gingivalis and Alzheimer disease: Recent findings and potential therapies.

Epidemiological studies have identified an association between periodontitis and Alzheimer disease (AD); however, the nature of this association has been unclear. Recent work suggests that brain colonization by the periodontal pathogen Porphyromonas gingivalis may link these two inflammatory and degenerative conditions. Evidence of P. gingivalis infiltration has been detected in autopsy specimens from the brains of people with AD and in cerebrospinal fluid of individuals diagnosed with AD. Gingipains, a class of P. gingivalis proteases, are found in association with neurons, tau tangles, and beta-amyloid in specimens from the brains of individuals with AD. The brains of mice orally infected with P. gingivalis show evidence of P. gingivalis infiltration, along with various neuropathological hallmarks of AD. Oral administration of gingipain inhibitors to mice with established brain infections decreases the abundance of P. gingivalis DNA in brain and mitigates the neurotoxic effects of P. gingivalis infection. Thus, gingipain inhibition could provide a potential approach to the treatment of both periodontitis and AD.

Nonsurgical Periodontal Therapy in CKD: Findings of the Kidney and Periodontal Disease (KAPD) Pilot Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Observational studies have suggested that periodontal disease may be a modifiable risk factor for chronic kidney disease (CKD). The Kidney and Periodontal Disease (KAPD) Study was designed to determine the feasibility of conducting a periodontal disease treatment trial among a high-risk (mostly poor and racial/ethnic minority) population and estimate the magnitude and variability of kidney and inflammatory biomarker levels in response to intensive periodontal treatment. STUDY DESIGN: Single-center, unmasked, intention-to-treat, randomized, controlled, pilot trial with 2:1 allocation to the treatment and comparison groups. SETTING & PARTICIPANTS: English- and Spanish-speaking individuals aged 20 to 75 years receiving primary care within the San Francisco Community Health Network with evidence of both moderate to severe periodontal disease and CKD. INTERVENTION: Immediate intensive nonsurgical periodontal treatment versus rescue treatment for progressive disease at baseline and 4, 8, and 12 months. OUTCOMES: Feasibility and process outcomes. Levels of biomarkers of kidney function, kidney injury, and systemic inflammation obtained at baseline and 4 and 12 months. RESULTS: KAPD randomly assigned 51 participants to the immediate (34 participants) or rescue (17 participants) groups. 14% dropped out of the study (4 immediate, 3 rescue) and 80% completed all 4 visits of the 12-month protocol (28 immediate, 13 rescue). Fewer than half the teeth recommended for extraction were extracted and 40% of immediate group visits were outside the protocol window. Bleeding on probing and probing depth improved more in the immediate group than in the rescue group; there was no significant separation in periodontal status. Levels of markers of vascular endothelial and systemic injury declined in both groups. LIMITATIONS: No true control group. CONCLUSIONS: This 12-month, pilot, randomized, controlled trial successfully recruited and retained a high-risk population but was less successful observing treatment adherence, treatment effect, and variability of biomarker levels. Although KAPD did not meet all of its goals, important lessons learned can be applied to future studies. FUNDING: National Institute of Diabetes and Digestive and Kidney Disease (Bethesda, MD; grant number 1K23DK093710-01A1) and Harold Amos Medical Faculty Development Program of the Robert Wood Johnson Foundation, Princeton, NJ. Funders had no role in study design; collection, analysis, or interpretation of data; writing the report; or the decision to submit the report for publication. TRIAL REGISTRATION: NCT01802216.

Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388.

COR388, a small-molecule lysine-gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine-gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28-day dose-response study, COR388 inhibited the lysine-gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine-gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine-gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine-gingipain and eliminating P. gingivalis infection in humans.